Contactin Associates with Sodium Channel Nav1.3 in Native Tissues and Increases Channel Density at the Cell Surface

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Abstract
The upregulation of voltage-gated sodium channel Nav1.3 has been linked to hyperexcitability of axotomized dorsal root ganglion (DRG) neurons, which underlies neuropathic pain. However, factors that regulate delivery of Nav1.3 to the cell surface are not known. Contactin/F3, a cell adhesion molecule, has been shown to interact with and enhance surface expression of sodium channels Nav1.2 and Nav1.9. In this study we show that contactin coimmunoprecipitates with Nav1.3 from postnatal day 0 rat brain where this channel is abundant, and from human embryonic kidney (HEK) 293 cells stably transfected with Nav1.3 (HEK-Nav1.3). Purified GST fusion proteins of the N and C termini of Nav1.3 pull down contactin from lysates of transfected HEK 293 cells. Transfection of HEK-Nav1.3 cells with contactin increases the amplitude of the current threefold without changing the biophysical properties of the channel. Enzymatic removal of contactin from the cell surface of cotransfected cells does not reduce the elevated levels of the Nav1.3 current. Finally, we show that, similar to Nav1.3, contactin is upregulated in axotomized DRG neurons and accumulates within the neuroma of transected sciatic nerve. We propose that the upregulation of contactin and its colocalization with Nav1.3 in axotomized DRG neurons may contribute to the hyper-excitablity of the injured neurons.